US4379792A - Anti-inflammatory composition - Google Patents

Anti-inflammatory composition Download PDF

Info

Publication number
US4379792A
US4379792A US06332434 US33243481A US4379792A US 4379792 A US4379792 A US 4379792A US 06332434 US06332434 US 06332434 US 33243481 A US33243481 A US 33243481A US 4379792 A US4379792 A US 4379792A
Authority
US
Grant status
Grant
Patent type
Prior art keywords
carbon atoms
methyl
alkyl
oxo
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US06332434
Inventor
Edward H. Blaine
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14Oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/929Vasodilator

Abstract

A pharmaceutical composition containing an interphenylene 9-thia-11-oxo-12-aza prostanoic acid type renal vasodilator and a non-steroidal anti-inflammatory agent and its use are disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This is continuation-in-part of U.S. Application Ser. No. 316,625 filed Oct. 30, 1980, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with a pharmaceutical composition containing a renal vasodilator and a non-steroidal anti-inflammatory agent.

Non-steroidal anti-inflammatory agents are known (see e.g., U.S. Pat. Nos. 3,161,654, 3,654,349, 3,647,858). A specific example of this class of compounds is the commercial product known as indomethacin.

Recently, a novel class of prostanoic acid type compounds having pharmacological activity have been disclosed (U.S. Pat. No. 4,225,609). These compounds are especially effective renal vasodilators.

It has been discovered that the combination of these renal vasodilator compounds and the non-steroidal anti-inflammatory agents produces a composition having enhanced pharmacological activity.

SUMMARY OF THE INVENTION

A pharmaceutical composition containing an interphenylene-9-thia-11-oxo-12-aza-prostanoic acid type renal vasodilator and a non-steroidal anti-inflammatory agent.

DETAILED DESCRIPTION OF THE INVENTION

An embodiment of the invention is a pharmaceutical composition useful for treating inflammation containing (i) a renal vasodilator compound of the formula ##STR1## wherein R is carboxy, a carboxy salt, a carboxy ester of the formula COOR5 wherein R5 is C1-10 alkyl, or CONHR6 wherein R6 is amino or methylsulfonyl;

A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent, or 2,5-thienylene or 2,5-furylene;

n is 3 or 4;

m is 0, 1, or 2;

R1 is hydrogen, deuterium, or methyl;

Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms;

R2 is hydrogen or lower alkanoyl;

R3 is hydrogen or straight chain C1-3 alkyl; and

R4 is lower straight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or R3 and R4 taken together with the carbon atom connecting R3 or R4 is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms;

and (ii) a non-steroidal anti-inflammatory compound.

A preferred (i) compound has the formula ##STR2## wherein X is chlorine or methyl;

r is 0, 1, or 2;

n is 3 or 4;

R1 is hydrogen, deuterium, or methyl;

Z is ethylene, trimethylene, cis or transpropenylene, or propynylene;

R3 is hydrogen or lower alkyl of 1-3 carbon atoms; and

R4 is 4-pentenyl, 5,5,5-trifluoropentyl, or lower straight or branched chain alkyl of 3-7 carbon atoms,

or ##STR3## wherein X is chlorine or methyl;

r is 0, 1, or 2;

n is 3 or 4;

m is 0, 1, or 2;

R1 is hydrogen, deuterium, or methyl;

Z is ethylene, trimethylene, propenylene, or propynylene;

y is 0, 2, or 3; and

W is polymethylene of 2-6 carbon atoms.

A more preferred (i) compound is selected from

4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]-propyl]benzoic acid and

4-[3-[3-[2(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid.

and individual isomers thereof. A still more preferred (i) compound is the (+) enantiomer of 4-[3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-propyl]benzoic acid.

Non-steroidal anti-inflammatory compounds are exemplified by indomethacin, ibuprofen, naproxen, piroxicam and the like. A preferred non-steroidal antiinflammatory compound is indomethacin.

The composition may contain varying amounts of (i) and (ii). The weight ratio of (i):(ii) may range from 1.7:1 to 1:26; preferably from 1:1 to 1:26; more preferably from 1:7 to 1:26; and most preferably from 1:15 to 1:26. In addition to the active ingredients (i) and (ii) the composition may also contain other conventional pharmaceutically acceptable compounding ingredients, as necessary or desired. Such ingredients are generally referred to as carriers or diluents. Conventional procedures for preparing such compositions in appropriate dosage forms may be utilized. Whatever the dosage form, it will contain a therapeutically effective amount of the present composition.

The present compositions may be administered orally or other than orally e.g., parenterally, by insufflation, topically, rectally, etc.; using appropriate dosage forms, e.g., tablets, capsules, suspensions, solutions and the like for oral administration, suspension emulsions and the like for parenteral administration; ointments and the like for topical administration.

Treatment dosage for human beings may be varied as necessary. Generally, daily dosages of the present composition may range from about 550 to about 27 mg; preferably from 400 to about 60 mg; more preferably from about 200 to about 120 mg, using the appropriate dosage form and mode of administration.

The present compositions provide for an improved method of treating inflammation in patients who may have or may develop impaired renal function. It is known that administration of a non-steroidal, anti-inflammatory agent such as indomethacin may result in reducing renal function of a human patient. Where the patient already has renal function impaired, of course, the non-steroidal anti-inflammatory might cause further impairment-and, thus, this patient would be denied the benefit of the inflammation relief offered by the non-steroidal inflammatory.

In vivo testing in test animals (dogs) has demonstrated that the present compositions prevent (or restore) impairment of renal function. Specifically, indomethacin alone when administered intravenously to test animals decreased effective renal plasma flow (ERPF) by about 37% and glomelular filtration rate (GFR) by about 28%, two criteria of renal function. When 4-[3-[3-([2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid, was administered to the test animals after the indomethacin, GFR was restored to normal within about two hours and the ERPF rose to almost twice the preindomethacin treatment level. The restoration of the GFR is especially surprising and coupled with the increase in ERPF indicates that the present compositions can be used in patients, requiring anti-inflammatory therapy without impairing renal function.

The formula I compounds are fully disclosed in U.S. Pat. No. 4,225,609 and to the extent necessary that disclosure is incorporated herein by reference.

A proces for preparing the individual enantiomers of the formula I compounds is illustrated by the following examples. The underlined numbers in Example 1 identify the products as shown in the Flow Sheet.

EXAMPLE 1 Resolution of Racemic 4-{3-[3-[2-(1-hydroxycyclohexyl)-ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic Acid ##STR4## Step A. Preparation of (±)-Methyl 4-[3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoate (2)

To a freshly-prepared solution of (±)-4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid (1) (10 g, 25.6 mmol) in dry N,N-dimethylformamide (86 ml) contained in a 250 ml round bottom flask is added finely-ground potassium carbonate (3.54 g, 25.6 mmol) followed by methyl iodide (1.6 ml, 25.6 mmol). The resulting suspension is protected from atmospheric moisture with a magnesium sulfate drying tube and is stirred at room temperature for 19.5 hours. The reaction mixture is poured into water (175 ml) contained in a separatory funnel and then is extracted with ether (3×40 ml). The organic extracts are combined, washed with saturated aqueous sodium bicarbonate (3×30 ml), dried over sodium sulfate and filtered. Evaporation (in vacuo) of the filtrate leaves the desired ester 2 as a pale yellow oil (10.55 g): tlc, Rf =0.4 (homogeneous, UV detection) on silica gel with ethyl acetate:hexane (7:3; v:v) as eluent; ir (2% solution in chloroform) 3400 (w), 1710 (s), 1600 (s) and 1280 (s) cm-1.

Step B. Preparation of Methyl 4-[3-[3-[2-(1-(-)-camphanyloxy)cyclohexyl)-ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoate (3)

To a solution of (±)-methyl 4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]-benzoate (2) (38.37 g, 94.6 mmol) in methylene chloride (189 ml) are added (-)-camphanic acid (20.64 g, 104.1 mmol) and 4-dimethylaminopyridine (5.77 g, 47.3 mmol). The resulting solution is cooled to 0° C. and treated with a solution of N,N'-dicyclohexylcarbodiimide (23.38 g, 113.52 mmol) in methylene chloride (180 ml) added slowly with stirring over 15 minutes. Thereby is obtained a heterogeneous mixture which is stirred at ambient temperature for 22 hours. The reaction mixture is filtered to remove the insoluble solid (N,N'-dicyclohexylurea). The filtrate is washed with 0.2 N-hydrochloric acid (2×60 ml) and water (2×80 ml), dried over sodium sulfate and filtered. Evaporation (in vacuo) of the filtrate affords a brown, oily residue (semi-solid): tlc on silica gel with chloroform:methanol (98:2; v:v) indicates that the product 3, Rf =0.3, is accompanied by starting material 2 (ca. 5%) and traces of 4-dimethylaminopyridine.

The oily residue is "flash chromatographed" on silica gel (600 g, 230-400 mesh, E. Merck) using chloroform-methanol (98:2; v:v) as eluent and a flow rate sufficient to move the solvent front at 1" per minute. Thereby is eluted product 3 (ca. 55 g as a yellow solid) which is contaminated with N-((-)-camphanyl)-N,N'-dicyclohexylurea (4). Product 3 is used as such in Step C described below.

Step C. Separation of Mixture 3 Into Diastereomeric Components (-,-)-3 and (+,-)-3

(a) Isolation of (-,-)3-Yellow solid 3 (ca. 55 g from Step B above) is triturated with ethyl acetate hexane (1:1; v:v; 300 ml) at room temperature for 1 hour to provide a heterogeneous mixture which is filtered. The collected, pale yellow solid (ca. 25 g of impure (-,-)-3) is recrystallized six times from ethyl acetate to afford pure diastereomer1 (-,-)-3 as colorless crystals (8.85 g), mp 163°-164° C.; [α]D 22 =-47.3° (c 0.58, CHCl3).

(b) Isolation of (+,-)-3--The trituration filtrate from Step C (a) above is evaporated in vacuo to provide a residue2 (ca. 24 g) consisting essentially of (+,-)-3 and byproduct 4. This residue is "flash chromatographed" in two separate 12 g portions as described below. A 12 g portion is applied in chloroform to a silica gel column (ca. 350 g, 230-400 mesh, E Merck, 60 mm in diameter×10" in length) which is eluted first with 30% ethyl acetate in hexane (2.4 L) at a flow rate sufficient to move the solvents from 1" per minute to remove the byproduct 4. Continued elution at the same flow rate with 40% ethyl acetate in hexane (1 L), 50% ethyl acetate in hexane (2 L) and 60% ethyl acetate in hexane (1 L) provides (+,-)-3. From the two "flash chromatographies" is obtained a pale yellow solid (15 g), [α]D 22 =+26.5° (c 0.57, CHCl3). This solid is recrystallized from ethyl acetate to constant rotation. Thereby is obtained pure diastereomer (+,-)-33 as colorless crystals (10.55), mp 130°-132° C.; [α]D 22 =+37.2° (c 0.61, CHCl3).

Step D. Hydrolysis of (+,-)-3 and (-,-)-3 (a) Preparation of (+)-4-3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4 -oxo-2-thiazolidinyl]-propyl benzoic Acid

To toluene (102 ml) contained in a 250 ml round bottom flask is added crushed solid potassium hydroxide (3.83 g, 68.3 mmol). The resulting heterogeneous mixture is heated at reflux until ca. 20 ml of distillate is collected4 and then is cooled to room temperature. To the cooled heterogeneous mixture is added (+,-)-3 (4 g, 6.83 mmol) followed by dicyclohexyl-18-Crown-6 (12.72 g, 34.2 mmol). The resulting reaction mixture is protected from atmospheric moisture with a magnesium sulfate drying tube and is vigorously stirred and heated at 40° C. (oil bath) for 1 hour. Then the drying tube is removed, water (80 ml) is added to the brown reaction mixture and stirring and heating at 40° C. are continued for 45 hours. After cooling to room temperature, the reaction mixture is poured slowly into cold, excess N hydrochloric acid (200 ml) with vigorous stirring. The acidic,5 aqueous mixture is transferred to a separatory funnel and the layers are allowed to separate. The aqueous layer (acidic phase) is extracted with chloroform (4×100 ml). The toluene and chloroform layers are combined, washed with water (2×100 ml), dried over sodium sulfate and filtered. Evaporation (in vacuo) of the filtrate leaves an oily residue which is triturated with ether at room temperature to afford an insoluble, colorless solid. The solid is collected, washed with ether and dried to give 2.04 g (76%) of (+)-1: tlc, Rf =0.26 (homogeneous, UV detection) with chloroform:methanol (9:1; v:v) on silica gel; identical by tlc to 1. Recrystallization from methanol affords pure enantiomer (+)-1 as colorless crystals (1.1 g), mp 139.5-140.5° C.; [α]D 22 +70.0° (c 0.47, CHCl3); ir (KBr pellet) 3270, 1690, 1640 and 1260 cm1 ; pmr (CDCl3) 8.05 (2H, d), 7.28 (2H, d), 6.49 (2H, bs, OH and CO2 H), 4.75 (H, bm), 3.56 (2H,s), 2.68 (2H, t) and 1.60 (bc envelope).

Anal. Calcd. for C21 H29 NO4 S: C, 64.42; H, 7.47; N, 3.58 Found: C, 64.57; H, 7.81; N, 3.51

(b) Preparation of (-)-4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic Acid

The hydrolysis of the pure diastereomer (-,-)-3 is carried out exactly as described above for (+,-)-3 in Step D (a). Thereby is obtained pure enantiomer (-)-1 as colorless crystals (1.24 g), mp 140°-141° C. (from CH3 OH); [α]D 22 -68.7° (C 0.47, CHCl3); tlc, ir and pmr data identical with those recorded for (+)-1.

Anal. Calcd. for C21 H29 NO4 S: C, 64.42; H, 7.47; N, 3.58 Found: C, 64.48; H, 7.72; N, 3.72

EXAMPLE 2 (A) Preparation of Methyl 4-[3-[3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoatebenzoic

A solution of racemic 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoic acid (13.13 g; 0.03336 mole) in dimethylformamide (66 ml) is treated with potassium carbonate (9.22 g; 0.06672 mole) and methyliodide (5.68 g; 0.04003 mole) and the resulting mixture is stirred at room temperature for 22 hours.

The reaction mixture is poured into cold water (330 ml). The oily layer is extracted with ether. The combined extracts are washed well with water and dried over magnesium sulfate. The solvent is removed under vacuum to give the methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate racemate as an orange oil, yield 13.60 g.

(B) Separation of the Two Racemic Modifications of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate

The two racemic modifications that comprise methyl 4-[3-[3-(3-hydroxyoctyl-4-oxo-2-thiazolidinyl]propyl]benzoate as obtained above in A are separated by liquid chromatography using a Prep LC/System 500 liquid chromatograph manufactured by Waters Associate, Inc. The chromatographic column in this instrument is a Prep PAK-500/C18 silica cartridge with dimensions 5.7×30 cm. The solvent mixture used is hexane-isopropyl alcohol, 95:5 (v/v). Thirteen g of the mixed racemates of the methyl ester after elution with 60 L of the solvent system gives 4.8 g of a front running fraction designated Racemate B-methyl ester and 6.9 g of a slower running fraction designated Racemate A-methyl ester. The two fractions can also be differentiated by thin layer chromatography on silica with 2% methanol in chloroform (v/v) as the mobile phase. In this system, Racemate B-methyl ester has Rf 0.32, and Racemate A-methyl ester has Rf 0.28.

(C-1) Preparation of Diastereomeric Camphanates from Racemate A of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate

N,N'-Dicyclohexylcarbodiimide (6.2 g, 30 mmole) in CH2 Cl2 is added to a solution at 0° C. of Racemate A of methyl 4[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate (10.0 g, 24.6 mmole), (15)-(-)- -camphanic acid (5.39 g, 27.2 mmole) and 4-dimethylaminopyridine (1.5 g, 12.3 mmole) in CH2 Cl2 (25 ml). The mixture is stirred at 27° C. for 6 hours. Precipitated dicyclohexylurea is removed by filtration. The filtrate is washed with 0.1 N hydrochloric acid and dried. Removal of solvent gave the crude mixed diastereomeric camphanates of Racemate A-methyl ester.

(C-2) Preparation of Diastereomeric Camphanates from Racemate B of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate

By following the procedure described in Step C-1 but substituting Racemate B-methyl ester for the Racemate A-methyl ester there is obtained the crude mixed diastereomeric camphanates of Racemate B-methyl ester.

(D-1) Isolation of the Levorotatory Diasteromeric Camphanate of Racemate A of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate

The crude mixed diastereomeric camphanates or Racemate A-methyl ester (Step C-1) are triturated with 1:1 ethyl acetate-hexane (100 ml of solvent mixture per 15 g of esters). The insoluble material is collected on a filter. The filtrate containing the bulk of the dextrorotatory diastereomer is set aside. The solid is recrystallized three times from ethyl acetate to give the levorotatory diastereomeric camphanate of Racemate A-methyl ester (chemical name: (-)-diastereomer of racemate A methyl 4-[3-[3-(15)- -camphanyloxy)octyl]-4-oxo-2-thiazolidinyl]propyl]benzoate).

(D-2) Isolation of the Dextrorotatory Diastereomeric Camphanate of Racemate A of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]-benzoate

Evaporation of solvents from the filtrate obtained by trituration of mixed diastereomeric camphanate of racemate A-methyl ester gives an oil which crystallizes on standing. This solid is recrystallized three times from ethyl acetate to yield the dextrorotatory diastereomeric camphanate of racemate A-methyl ester. (Chemical name: (+)-diastereomer of racemate A methyl 4-[3-[3-(3-((15)- -camphanyloxy-octyl)-4-oxo-2-thiazolidinyl]propyl]benzoate). (D-3) Isolation of the Levorotatory Diastereomeric Camphanate of Racemate B of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoate

Treatment of the crude mixed diastereomeric camphanates of Racemate B-methyl ester (Step C-2) exactly as in D-1 yields the levorotatory diastereomeric camphanate of Racemate B-methyl ester (chemical name: (-)-diastereomer or racemate B-methyl 4-[3-[3-(3-((15)- -camphanyl-oxy)octyl-4-oxo-2-thiazolidinyl]propyl benzoate).

(D-4) Isolation of the Dextrorotatory Diastereomeric Camphanate of Racemate B of Methyl 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]-benzoate

Treatment of the filtrate from the isolation of the camphanate of D-3 exactly as described in Step D-2 yields the dextrorotatory diastereomeric camphanate of Racemate B-methyl ester (chemical name: (+)-diastereomer or racemate B-methyl 4-[3-[3-(3-((15)- -camphanyloxy)octyl)-4-oxo-2-thiazolidinyl]propyl]benzoate.

(E-1) Preparation of the (-)-Enantiomer of Racemate A of 4-[3-[3-(3-hydroxyoctyl-4-oxo-2-thiazolidinyl]propyl]benzoic acid

Potassium hydroxide (finely crushed pellets) (3.83 g,, 68.3 mmoles) is added to toluene (100 ml). The mixture is stirred and treated with the levorotatory diastereomeric camphanate of Racemate A-methyl ester (D-1) (4 g, 6.82 mmoles) and dicyclohexyl-18-crown-6 (12.7 g, 34.2 mmole). The mixture is then stirred and heated at 40° C. for 1 hour. Water (80 ml) is added to the reaction mixture and stirring at 40° C. is continued for 45 hours. The mixture is then poured into 1 N hydrochloric acid (200 ml). The toluene layer is separated, washed with water and dried. The solvent is evaporated at reduced pressure. The residual oil is triturated with acetonitrile to give the waxy solid (-)-enantiomer of racemate A of 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]-benzoic acid.

(E-2) Preparation of the (+)-Enantiomer of Racemate A of 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazol-idinyl]propyl benzoic acid

Hydrolysis of the dextrorotatory diastereomeric camphanate of Racemate A-methyl ester (Step D-2) exactly as described in Step E-1 yields the waxy solid (+)-enantiomer of Racemate A of 4-[3-[3-(3-hydroxyoctyl-4-oxo-2-thiazolidinyl]propyl]benzoic acid.

(E-3) Preparation of the (-)-Enantiomer of Racemate B of 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoic acid

Hydrolysis of the levorotatory diastereomeric camphanate of Racemate B-methyl ester (Step D-3) exactly as described in Step E-1 yields the waxy solid (-)-enantiomer of Racemate B of 4-[3-[3-(3-hydroxyoctyl-4-oxo-2-thiazolidinyl]propyl]benzoic acid.

(E-4) Preparation of the (+)-Enantiomer of Racemate B of 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoic acid

Hydrolysis of the dextrorotatory diastereomeric camphanate of Racemate B-methyl ester (Step D-4) exactly as described in Step E-1 yields the waxy solid (+)-enantiomer of Racemate B of 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoid acid.

Claims to the invention follow.

Claims (6)

I claim:
1. A pharmaceutical composition useful for treating inflammation containing (i) a renal vasodilator compound of the formula ##STR5## wherein R is carboxy, a carboxy salt, a carboxy ester of the formula COOR5 wherein R5 is C1-10 alkyl,, or CONHR6 wherein R6 is amino or methylsulfonyl;
A is a p-phenylene or a m-phenylene or substituted phenylene derivative in which one or two of the phenylene hydrogens is replaced by a methyl or a halo substituent;
n is 3 or 4;
m is 0, 1, or 2;
R1 is hydrogen, deuterium, or methyl;
Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms;
R2 is hydrogen or lower alkanoyl;
R3 is hydrogen or straight chain C1-3 alkyl; and
R4 is lower straight chain or branched alkyl having from 3-7 carbon atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and lower alkoxy methylene; or
R3 and R4 taken together with the carbon atom connecting R3 and R4 is a cyclic substituent selected from a bridged or unbridged alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing sulfur or oxygen and from 5-7 ring-forming carbon atoms. and (ii) inclomethacin wherein the weight ratio i:ii ranges from 1.7:1 to 1:26.
2. The composition of claim 1 wherein said (i) compound has the formula ##STR6## wherein X is chlorine or methyl
r is 0, 1, or 2;
n is 3 or 4;
R1 is hydrogen, deuterium, or methyl;
Z is ethylene, trimethylene, cis or trans-propylene, or propynylene;
R3 is hydrogen or lower alkyl of 1-3 carbon atoms; and
R4 is 4-pentenyl, 5,5,5-trifluoropentyl, or lower straight or branched chain alkyl of 3-7 carbon atoms
or ##STR7## wherein X is chlorine or methyl
r is 0, 1, or 2;
n is 3 or 4;
m is 0, 1, or 2;
R1 is hydrogen, deuterium, or methyl
Z is ethylene, trimethylene, propenylene, or propynylene;
y is 0, 2, or 3; and
W is polymethylene of 2-6 carbon atoms.
3. The composition of claim 2 wherein said (i) compound is 4-[3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl]benzoic acid.
4. The composition of claim 2 wherein said (i) compound is 4-[3-[3-(2-(1-hydroxycyclohexyl)-ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid.
5. The composition of claim 4 wherein said (i) compound is the (+) enantiomer.
6. A method of treating inflammation in a human which comprises administering to said human a composition of claim 1.
US06332434 1980-10-30 1981-12-21 Anti-inflammatory composition Expired - Fee Related US4379792A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US31662580 true 1980-10-30 1980-10-30
US06332434 US4379792A (en) 1980-10-30 1981-12-21 Anti-inflammatory composition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06332434 US4379792A (en) 1980-10-30 1981-12-21 Anti-inflammatory composition

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US31662580 Continuation-In-Part 1980-10-30 1980-10-30

Publications (1)

Publication Number Publication Date
US4379792A true US4379792A (en) 1983-04-12

Family

ID=26980516

Family Applications (1)

Application Number Title Priority Date Filing Date
US06332434 Expired - Fee Related US4379792A (en) 1980-10-30 1981-12-21 Anti-inflammatory composition

Country Status (1)

Country Link
US (1) US4379792A (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0114172A1 (en) * 1983-01-24 1984-08-01 Merck & Co., Inc. Anti-inflammatory composition
US4472384A (en) * 1983-06-15 1984-09-18 Merck & Co., Inc. Antihypertensive composition
US4474811A (en) * 1981-12-24 1984-10-02 Kakenyaku Kako Co., Ltd. Anti-inflammatory ophthalmic solution and process for preparing the same
WO1994023748A1 (en) * 1993-04-08 1994-10-27 The University Of Queensland Administration of vaso-active agent and therapeutic agent
US20040208914A1 (en) * 2004-06-03 2004-10-21 Richlin David M. Topical preparation and method for transdermal delivery and localization of therapeutic agents

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3161654A (en) * 1962-01-05 1964-12-15 Merck & Co Inc alpha-(1-aroyl-3-indolyl) alkanoic acids
US3647858A (en) * 1970-05-01 1972-03-07 Merck & Co Inc Process for preparing 1-benzylidene-3-indenyl acetic acids
US3654349A (en) * 1970-05-01 1972-04-04 Merck & Co Inc Substituted indenyl acetic acids
US4225609A (en) * 1977-10-27 1980-09-30 Merck & Co., Inc. Interphenylene 9-thia-11-oxo-12-aza-prostanoic acids

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3161654A (en) * 1962-01-05 1964-12-15 Merck & Co Inc alpha-(1-aroyl-3-indolyl) alkanoic acids
US3647858A (en) * 1970-05-01 1972-03-07 Merck & Co Inc Process for preparing 1-benzylidene-3-indenyl acetic acids
US3654349A (en) * 1970-05-01 1972-04-04 Merck & Co Inc Substituted indenyl acetic acids
US4225609A (en) * 1977-10-27 1980-09-30 Merck & Co., Inc. Interphenylene 9-thia-11-oxo-12-aza-prostanoic acids

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chem. Abst. 89-(1978) 140967 H. *
Merck Index, 9th Ed. (1976) p. 176. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4474811A (en) * 1981-12-24 1984-10-02 Kakenyaku Kako Co., Ltd. Anti-inflammatory ophthalmic solution and process for preparing the same
EP0114172A1 (en) * 1983-01-24 1984-08-01 Merck & Co., Inc. Anti-inflammatory composition
US4472384A (en) * 1983-06-15 1984-09-18 Merck & Co., Inc. Antihypertensive composition
EP0129136A2 (en) * 1983-06-15 1984-12-27 Merck & Co., Inc. Antihypertensive composition
EP0129136A3 (en) * 1983-06-15 1987-11-11 Merck & Co. Inc. Antihypertensive composition
WO1994023748A1 (en) * 1993-04-08 1994-10-27 The University Of Queensland Administration of vaso-active agent and therapeutic agent
US5750141A (en) * 1993-04-08 1998-05-12 The University Of Queensland Administration of vaso-active agent and therapeutic agent
US20040208914A1 (en) * 2004-06-03 2004-10-21 Richlin David M. Topical preparation and method for transdermal delivery and localization of therapeutic agents
US20080293703A1 (en) * 2004-06-03 2008-11-27 Richlin David M Topical Preparation and Method for Transdermal Delivery and Localization of Therapeutic Agents
US7666914B2 (en) 2004-06-03 2010-02-23 Richlin David M Topical preparation and method for transdermal delivery and localization of therapeutic agents
US8211887B2 (en) 2004-06-03 2012-07-03 Richlin David M Topical preparation and method for transdermal delivery and localization of therapeutic agents

Similar Documents

Publication Publication Date Title
US4388312A (en) Quinone derivatives, their production and use
US5206261A (en) Oxindole derivative
US4233299A (en) 4-Hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides and salts thereof
US4172896A (en) Methane-sulfonamide derivatives, the preparation thereof and composition comprising the same
US4722810A (en) Enkephalinase inhibitors
US4714762A (en) Antiarteriosclerotic substituted benzimidazol-2-yl-and 3H-imidazo[4,5-b]pyridin-2-yl-phenoxy-alkanoic acids and salts and esters thereof
US4728650A (en) 3,4-dihydrobenzopyran derivatives and medicinal uses thereof
US4725691A (en) 2-[8-quinolinyl]-sulphinyl-1H-benzimidazole
US5124328A (en) Morpholine derivatives compositions and use
US4578390A (en) Hydroxybenzylamino derivatives as anti-inflammatory agents
US4559337A (en) 8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(alkoxy-containing acyl)hydrazides
US5180742A (en) Quinone derivatives, their production and use
US5416066A (en) 1,4-benzothiazepine derivatives
US4616025A (en) Thiazolidine derivatives, process for the preparation and pharmaceutical compositions thereof
US4579854A (en) Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril
US4025625A (en) Imidazothiazines
US4038411A (en) Antihypertensive amino acid esters
US4746669A (en) Substituted thiazoles as immunoregulants
US4134991A (en) Derivatives of 2-(3-phenyl-2-aminopropionyloxy)-acetic acid
EP0219436A2 (en) Thiazole derivative and leukotriene antagonist containing the same as the effective ingredients
WO2006024837A1 (en) Isoindolin-1-one derivatives
US4224342A (en) Guanidinobenzoic acid compounds and process for preparing the same
EP0283390A2 (en) Thiazole derivatives active on the cholinergic system, process for their preparation and pharmaceutical compositions containing them
JP2004067635A (en) Dgat inhibitor
EP0254545A2 (en) Diamine compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: MERCK & CO. INC., LINCOLN AVENUE, RAHWAY, NJ. A CO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:BLAINE, EDWARD H.;REEL/FRAME:004062/0202

Effective date: 19811218

SULP Surcharge for late payment
FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Expired due to failure to pay maintenance fee

Effective date: 19910414